The etiology of chronic fatigue syndrome (CFS), a disabling disorder affecting more than one million people in the United States (U.S.), is unknown. CFS appears to be a heterogeneous disorder with a variety of clinical presentations and postulated mechanisms. Several observations have suggested an association between CFS, immune dysregulation, autoimmune disorders (AID), and elevated risk of cancer, specifically non-Hodgkin's lymphoma (NHL). We have designed a molecular epidemiologic investigation to explore the role of genetic predisposition and specific immune factors in the etiology of CFS using a well-defined cohort of patients. We will also be studying the association between CFS and AID as well as the potential link between CFS and risk of cancer in general and NHL in particular among this population. The cases in our study will be ascertained from a pool of CFS cases diagnosed with acute onset following an infectious illness at Sierra Internal Medicine, a clinic in Nevada. Healthy (i.e., with no personal history of CFS, AID or cancer) unrelated controls have been ascertained and frequency-matched to cases by age, gender, ethnicity and geographic area. So far, 54 CFS cases fitting the criteria for diagnosis and 54 appropriately- matched controls have been pre-selected and will be approached for participation into the proposed study. In addition, we will identify healthy (i.e., with no personal history of CFS, AID or cancer) first- or second-degree relatives of CFS cases (at least one relative per case) who will be matched to cases by age, gender, ethnicity and geographic area for comparison to the cases and controls with respect to the immunologic factors pertaining to viral reactivation. Complete family health history and epidemiologic and medical information will be obtained on all participants through structured telephone interviews by a research assistant with training in genetic counseling. Cases and controls will be compared with respect to the prevalence of autoimmune disorders and specific types of cancer such as NHL among their extended relatives. Biological samples will be obtained from all subjects (cases, relatives of cases and the controls) for comparison with respect to the levels of antibodies against Epstein Barr Virus (EBV)-encoded proteins, namely EBV-encoded deoxyuridine triphosphate nucleotidohydrolase (dUTP- ase) and DNA polymerase. Our study has the potential to provide insight into the etiology of CFS and provide clues as to whether CFS is an AID through investigation of the potential genetic and immunologic link between CFS and AID among the family members. Furthermore, our study may provide insight into the association between CFS and NHL. The public health impact of our study stems from its potential to lead to early diagnosis and/or treatment of CFS, AID and NHL through understanding the etiologic link between these disorders and the role of genetic and immunologic factors.